Biomedical subjects

M E Stanton

Publications and source records attributed to M E Stanton.

At least 19 recordsLinked to original sources

PubMed2001

Perinatal exposure to polychlorinated biphenyls Aroclor 1016 or 1254 did not alter brain catecholamines nor delayed alternation performance in Long-Evans rats.

Several reports have indicated that polychlorinated biphenyls (PCB) altered development of biogenic amine systems in the brain, impaired behavioral performances, and disrupted maturation of the thyroid axis. The current study examines whether these developmental effects of PCB are correlated. Timed-pregnant Long-Evans rats were gavaged with the PCB mixture Aroclor 1016 (A-1016, 10 mg/kg) from gestation day (GD) 6 to parturition. Some pups continued to receive daily oral administration of PCB (10 mg/kg) until weaning at postnatal day (PD) 21. Another group of pregnant rats was given Aroclor 1254 (A-1254, 8 mg/kg) daily from GD 6 to weaning. At various age intervals, rats were sacrificed and six brain regions (prefrontal cortex, striatum, hippocampus, diencephalon, cerebellum, midbrain + brain stem) were removed and analyzed for dopamine (DA) and norepinephrine (NE) levels by high-performance liquid chromatography. In addition, transmitter turnover rates were determined after an acute treatment of alpha-methyl-p-tyrosine. Serum samples were collected and analyzed for triiodothyronine (T(3)) and thyroxine (T(4)) by radioimmunoassay. Behaviorally, rats were evaluated for spatial learning and memory by means of T-maze delayed alternation and Morris maze tasks on PD 23 and PD 70, respectively. A-1016 treatment produced only small and transient reductions in body weight gain, and generally did not alter the thyroid status of the developing rats. It did not cause any significant changes in DA or NE level, or turnover rate in any of the brain regions examined, nor did it affect behavioral measures of cognitive development. In contrast, perinatal exposure to A-1254 led to marked deficits of growth, and sharply reduced serum T(4), although T(3) remained largely unaffected. Accompanying this hormonal imbalance, brain NE contents in the A-1254-exposed pups were reduced, although brain DA was not significantly affected; no demonstrable neurobehavioral deficits were seen in the T-maze or Morris maze tests. These results indicated that development of central noradrenergic neurons was compromised by perinatal exposure to A-1254 but not A-1016, and both PCB mixtures failed to alter behavioral performances.

Animals↗

PubMed2001

Ontogenetic differences in the effects of unpaired stimulus preexposure on eyeblink conditioning in the rat.

Learned irrelevance (LIr) is a Pavlovian conditioning phenomenon in which random or unpaired preexposure to a conditional stimulus (CS) and to an unconditional stimulus (US) retards subsequent paired conditioning involving these stimuli. A previous developmental study of eyeblink conditioning in the rat suggested that LIr is not present on postnatal Day 20. Stanton, Fox, and Carter (1998) showed that unpaired preexposure to a CS and a US on postnatal Day 17 failed to retard (and, in fact, facilitated) subsequent paired conditioning involving these stimuli on postnatal Day 20. The present experiments were designed to further characterize the ontogeny of this phenomenon. In Experiment 1, LIr was observed when rat pups were tested for eyeblink conditioning as described in Stanton et al. (1998), except that preexposure occurred on postnatal Day 27, and acquisition testing occurred on postnatal Day 30. In Experiment 2, preexposure and acquisition both occurred on postnatal Day 30, and four types of preexposure were compared: chamber only, CS alone, US alone, or unpaired presentation of CS and US. Unpaired preexposure impaired acquisition relative to that of the remaining three groups, which did not differ. Experiment 3, showed that under the conditions of Experiment 2, LIr failed to appear on postnatal Day 20, but was observed on postnatal Days 25 and 30. These findings suggest that learning that events are unrelated emerges between postnatal Days 20 and 25 in the rat. Possible behavioral and neural mechanisms underlying this effect are discussed.

Animals↗

PubMed2001

Effects of early hippocampal lesions on trace, delay, and long-delay eyeblink conditioning in developing rats.

The effects of bilateral hippocampal aspiration lesions on later acquisition of eyeblink conditioning were examined in developing Long-Evans rat pups. Lesions on postnatal day (PND) 10 were followed by evaluation of trace eyeblink conditioning (Experiment 1) and delay eyeblink conditioning (Experiment 2) on PND 25. Pairings of a tone conditioned stimulus (CS) and periocular shock unconditioned stimulus (US, 100 ms) were presented in one of three conditioning paradigms: trace (380 ms CS, 500 ms trace interval, 880 ms interstimulus interval [ISI]), standard delay (380 ms CS, 280 ms ISI), or long delay (980 ms CS, 880 ms ISI). The results of two experiments indicated that hippocampal lesions impaired trace eyeblink conditioning more than either type of delay conditioning. In light of our previous work on the ontogeny of trace, delay, and long-delay eyeblink conditioning (Ivkovich, Paczkowski, & Stanton, 2000) showing that trace and long-delay eyeblink conditioning had similar ontogenetic profiles, the current data suggest that during ontogeny hippocampal maturation may be more important for the short-term memory component than for the long-ISI component of trace eyeblink conditioning. The late development of conditioning over long ISIs may depend on a separate process such as protracted development of cerebellar cortex.

Animals↗

PubMed2000

Multiple memory systems, development and conditioning.

A century of behavioral and neurobiological research suggests that Pavlovian conditioning involves three component memory systems: sensorimotor, affective and cognitive. In classical eyeblink conditioning, there is evidence that these three memory systems involve, respectively, the cerebellum, amygdala and hippocampus. This article reviews developmental research on eyeblink conditioning in rodents that is beginning to characterize ontogenetic dissociations and interactions among these memory systems. This research shows that the functional development of the affective system (conditioned fear response) precedes that of the sensorimotor system (conditioned eyeblink reflex). Modulation of these two systems by cognitive processes also seems to emerge at different points in ontogeny. Implications for cognitive development and research on multiple memory systems are discussed.

Animals↗

PubMed2000

Ontogeny of delay versus trace eyeblink conditioning in the rat.

The ontogeny of delay versus trace eyeblink conditioning was examined in 19-, 23-, and 30-day-old rat pups. Pairings of a tone conditioned stimulus (CS) and periocular shock unconditioned stimulus (US; 100-ms) were presented in one of three conditioning paradigms: standard delay [380-ms CS, 280-ms interstimulus interval (ISI)], trace (380-ms CS, 500-ms trace interval), or long-delay (980-ms CS, 880-ms ISI). The results of two experiments indicated that standard delay conditioning emerged between 19 and 23 days of age whereas trace and long-delay eyeblink conditioning emerged more slowly from postnatal Days 19 to 30. Because the acquisition profile for long-delay paralleled that of trace and not standard delay, it appears that the relative deficits in the emergence of trace eyeblink conditioning during development reflect difficulty in forming associations over long ISIs rather than the short-term memory demands of the trace conditioning paradigm.

Age Factors↗

PubMed1999

Ontogeny of eyeblink conditioning using a visual conditional stimulus.

The developmental emergence of associative learning in rodents is determined by interactions among sensory, motor, and associative systems that are engaged in a particular experimental preparation (Carter & Stanton, 1996; Hunt & Campbell, 1997; Rudy, 1992). In fear conditioning, chemosensory, auditory, and visual cues emerge successively as effective conditional stimuli (CS) during postnatal ontogeny. In the present study, we begin to examine the generality of this principle of sensory system development for eyeblink conditioning, a form of associative learning that develops substantially later than conditioned fear (Carter & Stanton, 1996). We asked whether the developmental emergence of eyeblink conditioning to a visual CS occurs at an age that is the same or different from conditioning to an auditory CS. In Experiment 1, rat pups were trained on postnatal Day 17 or 24 with experimental parameters (and design) that were identical to our previous studies of eyeblink conditioning except that presentation of a light rather than a tone served as the CS. The outcome was also identical: no eyeblink conditioning on Day 17 and strong conditioning on Day 24. In Experiment 2, conditioning to tone versus light was directly compared by means of a discrimination learning design on postnatal Days 19, 21, 23, and 31. There was no evidence for differential development of auditory versus visual eyeblink conditioning. The difference between this outcome and previous ones involving conditioned fear (Hunt & Campbell, 1997; Rudy, 1992) suggests that principles concerning sensory maturation and learning may be different for early- versus late-developing associative systems.

Amygdala↗

PubMed1998

Neonatal ethanol exposure impairs eyeblink conditioning in weanling rats.

Eyeblink conditioning depends on an identified brainstem-cerebellar circuit and may be useful in functional studies of early cerebellar damage produced by neurotoxicants. The present study asked whether binge-like neonatal ethanol exposure that damages the cerebellum would also result in eyeblink conditioning deficits. On postnatal day (PND) 23 to PND24, three groups of Long-Evans rat pups were tested for eyeblink conditioning: (1) ETOH, a group that received intragastric administration of 5.25 g/kg/day of ethanol on PND4 through PND9 via artificial rearing; (2) GC, a gastrostomy control group that received calorically matched milk formula on those days; and (3) SC, suckle controls that were reared normally with their dams. Eyeblink conditioning was severely impaired in the ethanol-treated group relative to the GC and SC groups, which did not differ. This impairment did not reflect sensory, motor, or motivational effects of ethanol treatment, because startle responses to the auditory conditioned stimulus and reflexive eyeblink responses to the unconditioned stimulus did not differ across the three treatment groups. These results suggest that neonatal binge ethanol exposure disrupted brain development in a manner that selectively impaired associative processes involved in eyeblink conditioning, consistent with alcohol-induced damage to the brainstem-cerebellar circuit necessary for this form of learning.

Animals↗

PubMed1995

Neonatal medial prefrontal lesions and recovery of spatial delayed alternation in the rat: effects of delay interval.

We have previously shown that rats given medial prefrontal lesions on postnatal Day 10 show a performance deficit on spatial delayed alternation (2-s delay) when tested between Days 19 and 23, but show recovery of function by Days 27-33 (Freeman & Stanton, 1992). The present study attempted to (a) examine the effects of extending the delay interval from 2 s to 15 or 45 s on the ontogeny of spatial delayed alternation; and (b) determine whether these longer delays would alter the ontogenetic profile of recovery from medial prefrontal damage. Animals were given medial prefrontal lesions (mPFC) or sham surgery on Day 10. They received acquisition training on delayed alternation with a 2-s delay on Day 21 or Day 28, followed by "probe" tests at delays of 15 and 45 s on the following day (Day 22 or Day 29). On Days 21-22 there was an overall effect of lesion at the 2-, 15-, and 45-s delay intervals indicating an early deficit. However, on Days 28-29 there was no effect of lesion at the end of acquisition or at the 15- or 45-s delay intervals. Recovery of memory function by mPFC animals on this task appears to occur during the weanling period regardless of delay interval.

Aging↗

PubMed1995

Ontogeny of eyeblink conditioning in the rat: auditory frequency and discrimination learning effects.

The present study sought to determine whether acoustic properties of the auditory conditioned stimulus (CS) or the use of a discrimination learning procedure would alter the emergence of eyeblink conditioning between postnatal Days 17 and 24 (Days 17-24) in the rat. In Experiment 1, we employed a 3 x 2 x 2 factorial design, involving pitch of the auditory CS (2.8, 5.0, and 9.0 kHz), training condition (paired vs. unpaired), and age (Days 17 or 24). Associative learning was evident at all tone frequencies on Day 24, but increased across frequencies on Day 17, although large age differences in conditioning remained at all tone frequencies. In Experiment 2, rat pups were trained to discriminate 2.8 versus 9.0-kHz tones on Day 17 or Day 24. Eyeblink conditioning increased with tone frequency on Day 24 but discriminative conditioning failed to appear on Day 17. These findings are discussed in relation to the role of auditory system maturation in the ontogeny of eyeblink conditioning.

Acoustic Stimulation↗

PubMed1995

Assessment of offspring development and behavior following gestational exposure to inhaled methanol in the rat.

The prospect of widespread human exposure associated with its use as an alternative fuel has sparked concern about the toxic potential of inhaled methanol (MeOH). Previous studies have revealed congenital malformations in rats following inhaled MeOH (Nelson et al. (1985). Fundam. Appl. Toxicol. 5, 727-736) but these studies did not include postnatal behavioral assessment. In the present study, pregnant Long-Evans rats were placed in exposure chambers containing 15,000 ppm MeOH or air for 7 hr/day on Gestational Days (GD) 7-19. The total alveolar dose of methanol was estimated at about 6.1 g/kg/day, for a total dose of about 42.7 g/kg for the entire study. Maternal body weights were recorded daily and blood methanol concentrations were determined at the end of exposure on GD 7, 10, 14, and 18. Following birth (Postnatal Day 0 [PND 0]), a number of tests were performed at various points in development, including: offspring mortality and body wt (PND 1,3), motor activity (PND 13-21, 30, 60), olfactory learning (PND 18), behavioral thermoregulation (PND 20-21), T-maze learning (PND 23-24), acoustic startle response (PND 24, 60), reflex modification audiometry (PND 60), pubertal landmarks (PND 31-56), passive avoidance (PND 72), and visual-evoked potentials (PND 160). Maternal blood MeOH levels, measured from samples taken within 15 min after removal from the exposure chamber, declined from about 3.8 mg/ml on the first day of exposure to 3.1 mg/ml on the 12th day of exposure. MeOH transiently reduced maternal body wt (4-7%) on GD 8-10, and offspring BW (5%) on PND 1. No other test revealed significant effects of MeOH. Prenatal exposure to high levels of inhaled MeOH appears to have little effect on this broad battery of tests beyond PND 1 in the rat.

Administration, Inhalation↗

PubMed1995

Early cerebellar lesions impair eyeblink conditioning in developing rats: differential effects of unilateral lesions on postnatal day 10 or 20.

Experiment 1 demonstrated that the ipsilateral cerebellar hemisphere is essential for the acquisition of eyeblink conditioning in infant rats and that cerebellar lesions given on Postnatal Day 10 (PND10) produced deficits in eyeblink conditioning when given to either hemisphere. For both hemispheres, lesions that were restricted to the cerebellar cortex produced less severe deficits than lesions that included the deep nuclei. Experiment 2 showed that the age at which the cerebellar lesions occurred determined whether damage to the contralateral cerebellar hemisphere impaired conditioning. Lesions of either the ipsilateral or contralateral hemisphere that included the deep nuclei disrupted eyeblink conditioning when given on PND10. In contrast, when lesions were given on PND20, ipsilateral lesions that included the deep nuclei abolished conditioning, while the same lesion given to the contralateral hemisphere had no effect.

Aging↗

PubMed1995

Disruption of cerebellar maturation by an antimitotic agent impairs the ontogeny of eyeblink conditioning in rats.

This study represents an attempt to establish a relationship between maturation of the cerebellum and the ontogeny of eyeblink conditioning in the rat. Experiments 1 and 2 examined the effects of disrupting cerebellar maturation by neonatal exposure to the antimitotic agent methylazoxymethanol (MAM) on the ontogeny of eyeblink conditioning in infant rats. Experiment 1 demonstrated that neonatal exposure to MAM on Postnatal Day 4 (PND4) and 7 severely disrupted cerebellar maturation. This effect appeared to be specific in that there was no overt dysmorphology in other brain regions. MAM treatment also severely disrupted associative eyeblink conditioning in rats given training on PND24 and 25. However, exposure to MAM had no effect on the unconditioned response, T-maze delayed alternation, or conditioned suppression of ongoing behavior. In Experiment 2, MAM was given on PND4 and 7 and pups were tested behaviorally on PND17-18, 20-21, or 31-32. Cerebellar hypoplasia was most dramatic shortly after exposure. The cerebellar cortex continued to mature after exposure to MAM, but development of morphological endpoints examined here were static from PND19 to 33. Eyeblink conditioning was impaired at all ages, indicating that there was no functional recovery following neonatal exposure to MAM over the age range tested. These experiments suggest that normal cerebellar maturation may be important for the ontogeny of eyeblink conditioning.

Animals↗

PubMed1994

Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice.

mGluR1 mutant mice are viable but show characteristic cerebellar symptoms such as ataxic gait and intention tremor. The anatomy of the cerebellum is not overtly disturbed. Excitatory synaptic transmission from parallel fibers (PFs) to Purkinje cells and that from climbing fibers (CFs) to Purkinje cells appear to be functional, and voltage-gated Ca2+ channels of Purkinje cells are normal. Both PF and CF synapses display normal short-term synaptic plasticity to paired stimuli. By marked contrast, long-term depression (LTD) is clearly deficient and conditioned eyeblink response is impaired. We conclude that mGluR1 is required for the induction of LTD and that the ataxic behavior and impaired eyeblink conditioning of the mGluR1 mutant mice are primarily due to deficient LTD.

Animals↗

PubMed1994

Cognitive and neuroanatomical effects of triethyltin in developing rats: role of age of exposure.

Long-Evans rat pups were injected i.p. on postnatal day 5 (PND5) or 12 with 0, 3, or 5 mg/kg triethyltin sulfate (TET) and then tested on T-maze delayed alternation on PND21 or 28. Delayed alternation learning was impaired on PND21 and 28 in pups given 5 mg/kg TET. Pups given 5 mg/kg TET on PND5 were more impaired on delayed alternation than pups given 5 mg/kg TET on PND12. Pups given 3 mg/kg TET on PND5 or 12 were unimpaired at either age of testing. On the day following training, pups were sacrificed for histological assessment employing Nissl- or immunohistochemical staining for glial fibrillary acidic protein (GFAP), a putative marker of gliosis. Pups given 5 mg/kg TET on PND5 showed increases in GFAP immunoreactivity (IR) in subiculum, amygdala, hippocampus, piriform cortex, and entorhinal cortex with concomitant decreases in Nissl-stained cells in these regions. Pups given 5 mg/kg TET on PND12 showed increases in GFAP IR in piriform cortex, amygdala and dorsal hippocampus with concomitant decreases in Nissl-stained cells in these regions. Exposure to 3 mg/kg TET on PND5 and PND12 produced a mild increase in GFAP IR in piriform cortex and amygdala but no discernible loss of Nissl-staining in these respective regions. TET-induced behavioral deficits appear related to damage of structural correlates of the human temporal lobe and not piriform cortical pathology. These results demonstrate that the day of exposure greatly influences the magnitude of the cognitive deficits and neuropathology associated with exposure to TET. There appears to be a critical period during postnatal development for the developmental neurotoxicity of this compound.

Animals↗

PubMed1994

Developmental neurotoxicity: evaluation of testing procedures with methylazoxymethanol and methylmercury.

Testing procedures for identification of potential developmental neurotoxicants were evaluated using two prototypical developmental neurotoxicants, methylazoxymethanol (MAM) and methylmercury (MeHg). Evaluation of offspring of Long-Evans rats incorporated assessments of developmental toxicity, neurochemistry, histology, and behavior, with most testing being completed near weaning. A number of endpoints in the testing strategy were sensitive to the effects of prenatal exposure to MAM [30 mg/kg on Gestation Day (GD) 15]: (1) MAM caused reduced neonatal body weights but did not effect viability or postnatal survivorship; (2) measurement of total and regional brain weight and histological analysis showed that a number of regions, the cortex and hippocampus in particular, were affected by MAM exposure; (3) an assay for glial fibrillary acidic protein (GFAP) showed that the concentration of this protein was significantly increased in the cortex and hippocampus of treated offspring; (4) a T-maze delayed-alternation procedure indicated that MAM-treated pups were slower in the acquisition phase of the task relative to control pups; (5) motor activity testing revealed hyperactivity in treated offspring that persisted into adulthood; and (6) acoustic startle procedures revealed reduced startle amplitudes in preweanlings. Few endpoints were significantly affected by prenatal MeHg exposure (1, 2, or 4 mg/kg on GD 6-15). High fetal and neonatal mortality and lower neonatal body weights were detected at the highest dose of MeHg. Although minimal effects of MeHg may reflect a relative insensitivity of the test species and/or the test methods, the combined results from both chemicals suggest that some procedures not currently required in the developmental neurotoxicity guideline may be useful in hazard identification, and further evaluation with other chemicals, species, strains, and/or exposure paradigms may be warranted.

Alkylating Agents↗

PubMed1994

Eyeblink conditioning in the infant rat: an animal model of learning in developmental neurotoxicology.

Classical conditioning of the eyeblink reflex is a relatively simple procedure for studying associative learning that was first developed for use with human subjects more than half a century ago. The use of this procedure in laboratory animals by psychologists and neuroscientists over the past 30 years has produced a powerful animal model for studying the behavioral and biological mechanisms of learning. As a result, eyeblink conditioning is beginning to be pursued as a very promising model for predicting and understanding human learning and memory disorders. Among the many advantages of this procedure are (a) the fact that it can be carried out in the same manner in both humans and laboratory animals; (b) the many ways in which it permits one to characterize changes in learning at the behavioral level; (c) the readiness with which hypotheses regarding the neurological basis of behavioral disorders can be formulated and tested; (d) the fact that it can be used in the same way across the life-span; and (e) its ability to distinguish, from normative groups, populations suffering from neurological conditions associated with impaired learning and memory, including those produced by exposure to neurotoxicants. In this article, we argue that these properties of eyeblink conditioning make it an excellent model system for studying early impairments of learning and memory in developmental neurotoxicology. We also review progress that has been made in our laboratory in developing a rodent model of infant eyeblink conditioning for this purpose.

Animals↗

PubMed1994

Time-dependent effects of acute chlorpyrifos administration on spatial delayed alternation and cholinergic neurochemistry in weanling rats.

On postnatal day 21 (PND21), Long-Evans rat pups received a single subcutaneous injection of either 0 (corn oil vehicle), 90, 120, or 240 mg/kg chlorpyrifos and were then tested for T-maze delayed alternation on PND23 or 26. Acetylcholinesterase (AChE) activity and muscaranic receptor density [i.e., quinuclidinyl benzilate (QNB) binding] were determined in hippocampus and cortex of brains taken from pups 15 hours after the end of behavioral testing (i.e., the morning of PND24, and 27). Pups exposed to the 240 mg/kg dose of chlorpyrifos showed signs of overt toxicity that precluded behavioral testing. Exposure to the 120 mg/kg dose produced a selective memory impairment (ie., a deficit in delayed alternation but not position discrimination) relative to the 90 mg/kg and vehicle groups. This impairment was transient, however, as it appeared on PND23 and was absent by PND26. PND21 exposure to chlorpyrifos produced dose-related inhibition and recovery of brain AChE over the PND24-27 age range. A similar pattern was observed in hippocampus. Binding of [3H]QNB was reduced in frontal cortex on PND27 only at the 240 mg/kg dose. No significant effects were observed in the hippocampus. These results suggest that the neurochemical effects of acute chlorpyrifos administration are more transient, and the behavioral effects are smaller and shorter-lived than what has been reported in adult rats.

Acetylcholinesterase↗

PubMed1993

Disruption of human eyeblink conditioning after central cholinergic blockade with scopolamine.

Human (Homo sapiens) volunteers (N = 72) received saline, a low dose of oral scopolamine (0.6 mg), a high dose of oral scopolamine (1.2 mg), or a peripheral analogue (glycopyrrolate). They then underwent classical conditioning of the eyeblink response to a tone conditioned stimulus (CS) and a corneal airpuff unconditioned stimulus (UCS) in a delay conditioning paradigm. There was a dose-related decline in acquisition of the conditioned response. These drug-induced conditioning deficits were similar to those previously reported in rabbit eyeblink conditioning and could not be attributed to such nonassociative factors as changes in auditory thresholds to the tone CS, magnitude of reflexive blinks to the airpuff UCS, or to changes in spontaneous blink rates.

Administration, Oral↗